Association between age at diagnosis and all-cause mortality in type 2 diabetes: the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study.

AIMS: It is unclear whether type 2 diabetes diagnosed in young adulthood is associated with increased severity than that occurring later in life beyond longer lifetime exposure to hyperglycemia. This study aimed at assessing the independent association of age at type 2 diabetes diagnosis with all-cause mortality. METHODS: This prospective cohort study enrolled 15,773 Caucasian patients with type 2 diabetes in 19 Italian centers in 2006-2008. Cardiometabolic risk profile and presence of complications and comorbidities were assessed at baseline and participants were stratified by quartiles of age at diabetes diagnosis. All-cause mortality was verified on 31 October 2015. RESULTS: Valid information on vital status was retrieved for 15,656 participants (99.3%). Patients in the lowest quartile had the longest diabetes duration, the worst glycemic control and the highest prevalence of insulin treatment, obesity, atherogenic dyslipidemia, and smoking habits. All complications were inversely associated with age at diabetes diagnosis after adjustment for age and sex, but not after further adjustment for diabetes duration. Percentages of death, Kaplan-Meier estimates, and unadjusted hazard ratios and mortality rates increased from the lowest to the highest quartile. In contrast, when adjusting for age and sex, participants falling in the lowest quartile, showed the highest mortality risk [hazard ratio 1.321 (95% confidence interval 1.196-1.460), P < 0.0001]. However, differences among quartiles disappeared after adjustment for diabetes duration, complications/comorbidities, or other cardiovascular risk factors. CONCLUSIONS: Type 2 diabetes onset in young adulthood is associated with increased mortality that is mainly driven by longer diabetes duration favoring the development of complications. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.

Impaired Remodeling of White Adipose Tissue in Obesity and Aging: From Defective Adipogenesis to Adipose Organ Dysfunction.

The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders.

Renal Expression and Localization of the Receptor for (Pro)renin and Its Ligands in Rodent Models of Diabetes, Metabolic Syndrome, and Age-Dependent Focal and Segmental Glomerulosclerosis.

The (pro)renin receptor ((P)RR), a versatile protein found in various organs, including the kidney, is implicated in cardiometabolic conditions like diabetes, hypertension, and dyslipidemia, potentially contributing to organ damage. Importantly, changes in (pro)renin/(P)RR system localization during renal injury, a critical information base, remain unexplored. This study investigates the expression and topographic localization of the full length (FL)-(P)RR, its ligands (renin and prorenin), and its target cyclooxygenase-2 and found that they are upregulated in three distinct animal models of renal injury. The protein expression of these targets, initially confined to specific tubular renal cell types in control animals, increases in renal injury models, extending to glomerular cells. (P)RR gene expression correlates with protein changes in a genetic model of focal and segmental glomerulosclerosis. However, in diabetic and high-fat-fed mice, (P)RR mRNA levels contradict FL-(P)RR immunoreactivity. Research on diabetic mice kidneys and human podocytes exposed to diabetic glucose levels suggests that this inconsistency may result from disrupted intracellular (P)RR processing, likely due to increased Munc18-1 interacting protein 3. It follows that changes in FL-(P)RR cellular content mechanisms are specific to renal disease etiology, emphasizing the need for consideration in future studies exploring this receptor's involvement in renal damage of different origins.

Independent association of estimated pulse-wave velocity with all-cause mortality in individuals with type 2 diabetes.

BACKGROUND: Estimated pulse wave velocity (ePWV), a surrogate measure of arterial stiffness, was shown to independently predict morbidity and mortality from cardiovascular disease and other causes in both the general population and high-risk individuals. However, in people with type 2 diabetes, it is unknown whether ePWV adds prognostic information beyond the parameters used for calculating it. AIMS: To assess the independent association of ePWV with all-cause mortality in individuals with type 2 diabetes. DESIGN: Prospective cohort study that enrolled 15,773 patients in 19 Italian centres in 2006-2008. METHODS: ePWV was calculated from a regression equation using age and mean blood pressure (BP). All-cause mortality was retrieved for 15,656 patients in 2015. RESULTS: Percentage and rate of deaths, Kaplan-Meier estimates, and unadjusted hazard ratios increased from quartile I to quartile IV of ePWV. After adjustment for age, sex, BP levels and anti-hypertensive treatment, the strength of association decreased but mortality risk remained significantly higher for quartiles II (+34%), III (+82%), and IV (+181%) versus quartile I and was virtually unchanged when further adjusting for other cardiovascular risk factors and complications/comorbidities. Each m·s - 1 increase in ePWV was associated with an increased adjusted risk of death in the whole cohort (+53%) and in participants with (+52%) and without (+65%) cardiorenal complications. Moreover, ePWV significantly improved prediction of mortality risk over cardiovascular risk factors and complications/comorbidities, though the net increase was modest. CONCLUSIONS: These findings suggest that ePWV may represent a simple and inexpensive tool for providing prognostic information beyond traditional cardiovascular risk factors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481, https://clinicaltrials.gov/ct2/show/NCT00715481.

Independent association of history of diabetic foot with all-cause mortality in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study.

BACKGROUND: Foot ulcers and/or infections are common long-term complications of diabetes and are associated with increased mortality, especially from cardiovascular disease, though only a few studies have investigated the independent contribution of these events to risk of death. This study aimed at assessing the association of history of diabetic foot with all-cause mortality in individuals with type 2 diabetes, independent of cardiovascular risk factors, other complications, and comorbidities. METHODS: This prospective cohort study enrolled 15,773 Caucasian patients in 19 Italian centers in the years 2006-2008. Prior lower extremity, coronary, and cerebrovascular events and major comorbidities were ascertained by medical records, diabetic retinopathy by fundoscopy, diabetic kidney disease by albuminuria and estimated glomerular filtration rate, cardiovascular risk factors by standard methods. All-cause mortality was retrieved for 15,656 patients on 31 October 2015. RESULTS: At baseline, 892 patients (5.7%) had a history of diabetic foot, including ulcer/gangrene and/or amputation (n = 565; 3.58%), with (n = 126; 0.80%) or without (n = 439; 2.78%) lower limb revascularization, and revascularization alone (n = 330; 2.09%). History of diabetic foot was associated with all-cause death over a 7.42-year follow-up (adjusted hazard ratio, 1.502 [95% confidence interval, 1.346-1.676], p < 0.0001), independent of confounders, among which age, male sex, smoking, hemoglobin A1c, current treatments, other complications, comorbidities and, inversely, physical activity level and total and HDL cholesterol were correlated independently with mortality. Both ulcer/gangrene and amputation alone were independently associated with death, with a higher strength of association for amputation than for ulcer/gangrene (1.874 [1.144-3.070], p = 0.013 vs. 1.567 [1.353-1.814], p < 0.0001). Both ulcer/gangrene/amputation and lower limb revascularization alone were independently associated with death; mortality risk was much higher for ulcer/gangrene/amputation than for revascularization (1.641 [1.420-1.895], p < 0.0001 vs. 1.229 [1.024-1.475], p = 0.018) and further increased only slightly for combined ulcer/gangrene/amputation and revascularization (1.733 [1.368-2.196], p < 0.0001). CONCLUSIONS: In patients with type 2 diabetes, an history of diabetic foot event, including ulcer/gangrene, amputation, and lower limb revascularization, was associated with a ~ 50% increased risk of subsequent death, independent of cardiovascular risk factors, other complications and severe comorbidities, which were also significantly associated with mortality. The association with mortality was greatest for amputation, whereas that for revascularization alone was relatively modest. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.

The "sweet" path to cancer: focus on cellular glucose metabolism.

The hypoxia-inducible factor-1α (HIF-1α), a key player in the adaptive regulation of energy metabolism, and the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), a critical regulator of glucose consumption, are the main drivers of the metabolic rewiring in cancer cells. The use of glycolysis rather than oxidative phosphorylation, even in the presence of oxygen (i.e., Warburg effect or aerobic glycolysis), is a major metabolic hallmark of cancer. Aerobic glycolysis is also important for the immune system, which is involved in both metabolic disorders development and tumorigenesis. More recently, metabolic changes resembling the Warburg effect have been described in diabetes mellitus (DM). Scientists from different disciplines are looking for ways to interfere with these cellular metabolic rearrangements and reverse the pathological processes underlying their disease of interest. As cancer is overtaking cardiovascular disease as the leading cause of excess death in DM, and biological links between DM and cancer are incompletely understood, cellular glucose metabolism may be a promising field to explore in search of connections between cardiometabolic and cancer diseases. In this mini-review, we present the state-of-the-art on the role of the Warburg effect, HIF-1α, and PKM2 in cancer, inflammation, and DM to encourage multidisciplinary research to advance fundamental understanding in biology and pathways implicated in the link between DM and cancer.

Sustained increase in physical fitness independently predicts improvements in cardiometabolic risk profile in type 2 diabetes.

AIMS: To investigate the relationship between changes in physical fitness and cardiovascular risk factors and scores in patients with type 2 diabetes receiving either a behavioural counselling intervention to increase moderate-to-vigorous-intensity physical activity (MVPA) and decrease sedentary-time (SED-time) or standard care. MATERIALS AND METHODS: This is a pre-specified ancillary analysis of the Italian Diabetes and Exercise Study_2, a 3-year randomized clinical trial in which 300 physically inactive and sedentary patients were randomized 1:1 to receive either a one-month theoretical and practical counselling each year or standard care. Mean changes from baseline throughout the 3-year period in MVPA, SED-time, cardiorespiratory fitness (VO2max ), muscle strength, flexibility, cardiovascular risk factors and scores were calculated for study completers (n = 267) and considered irrespective of study arm. RESULTS: Haemoglobin (Hb) A1c and coronary heart disease (CHD) risk scores decreased with quartiles of VO2max and lower body muscle strength changes. Multivariable linear regression analysis showed that increases in VO2max independently predicted decreases in HbA1c , blood glucose, diastolic blood pressure (BP), CHD and total stroke 10-year risk and increases in HDL cholesterol, whereas increases in lower body muscle strength independently predicted decreases in body mass index (BMI), waist circumference, triglycerides, systolic BP, CHD and fatal stroke 10-year risk. These associations remained after including changes in BMI, waist circumference, fat mass and fat-free mass, or MVPA and SED-time as covariates. CONCLUSIONS: Improvement in physical fitness predicts favourable changes in cardiometabolic risk profile, independent of changes not only in (central) adiposity or body composition but also in MVPA and SED-time. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01600937; URL https://clinicaltrials.gov/ct2/show/NCT01600937.

The Nutritional Quality of Food Provision at UK Government-Funded Holiday Clubs: A Cross-Sectional Analysis of Energy and Nutrient Content.

A large proportion of children are at risk of food insecurity during school holidays in the UK. The government-funded Holiday Activities and Food (HAF) programme provides free holiday clubs offering at least one healthy meal/day to eligible children and adolescents. This study aims at evaluating the nutritional quality of food provision at HAF holiday clubs, particularly hot/cold and vegetarian/non-vegetarian meals. Menu variants (n = 2759) from 49 HAF holiday clubs were assessed for adherence to School Food Standards (SFS) and their notional compositional quality, which was scored utilising a novel nutrient-based meal quality index. The median adherence to SFS across all available menus was 70% (IQR 59-79%). Overall, hot variants scored statistically higher menu quality scores than cold variants for both 5-11y (92.3 (80.7-102.7) vs. 80.4 (69.3-90.6)) and 11-18y (73.5 (62.5-85.8) vs. 58.9 (50.0-70.7)) criteria. Cold and hot menu variants tended to score differentially for quality sub-components. These findings highlight areas for potential future improvement in HAF holiday club provision with a tendency for food provision to appear less ideal for attendees for those aged 11-18. Ensuring that children from low-income households have access to a healthy diet is crucial to reduce UK health inequalities.

Retinopathy as an independent predictor of all-cause mortality in individuals with type 2 diabetes.

AIMS: To assess whether the presence and grade of diabetic retinopathy (DR) predict all-cause mortality, independent of risk factors for cardiovascular disease (CVD) and other complications, including diabetes-related kidney disease (DKD) and CVD, in individuals with type 2 diabetes mellitus. METHODS: Prospective cohort study that enroled 15,773 patients in 19 Italian centers in 2006-2008. DR ascertained by fundoscopy, DKD by albuminuria and estimated glomerular filtration rate, and prior CVD by hospital discharge records. All-cause mortality retrieved for 15,656 patients on 31 October 2015. RESULTS: The adjusted risk of death was increased in patients with any DR (hazard ratio, 1.136 [95% confidence interval, 1.054;1.224] P < 0.0001), advanced DR, including severe non-proliferative and proliferative DR and diabetic macula edema (1.213 [1.097;1.340] P < 0.0001), and especially proliferative DR alone (1.381 [1.207;1.580] P < 0.0001), compared with those without DR. The impact of DR was more evident in patients without than in those with DKD or CVD. Mortality risk was increased in participants with DR alone, though much less than in those with DKD or CVD alone and particularly in those with both DR and DKD or CVD. DR grade was related to mortality in individuals without DKD or CVD, whereas it conferred no additional risk to those with albuminuric or nonalbuminuric DKD or established CVD. CONCLUSIONS: In patients with type 2 diabetes mellitus, the excess mortality risk conferred by DR is relatively small and higher in those without DKD and CVD, suggesting that it may be mediated by the concurrent presence of these complications, even at a subclinical level.

Sustained decreases in sedentary time and increases in physical activity are associated with preservation of estimated ß-cell function in individuals with type 2 diabetes.

AIMS: In the Italian Diabetes and Exercise Study_2, a counselling intervention produced modest but sustained increments in moderate-to vigorous-intensity physical activity (MVPA), with reallocation of sedentary-time (SED-time) to light-intensity physical activity (LPA). This post hoc analysis evaluated the impact of intervention on estimated ß-cell function and insulin sensitivity. METHODS: Patients with type 2 diabetes were randomized to one-month counselling once-a-year or standard care for 3 years. The HOmeostatic Model Assessment-2 (HOMA-2) method was used for estimating indices of ß-cell function (HOMA-B%), insulin sensitivity (HOMA-S%), and insulin resistance (HOMA-IR); the disposition index (DI) was estimated as HOMA-ß%/HOMA-IR; MVPA, LPA, and SED-time were objectively measured by accelerometer. RESULTS: HOMA-B% and DI decreased in control group, whereas HOMA-B% remained stable and DI increased in intervention group. Between-group differences were significant for almost all insulin secretion and sensitivity indices. Changes in HOMA-B% and DI correlated with SED-time, MVPA and LPA. Changes in HOMA-B%, DI, and all indices were independently predicted by changes in SED-time (or LPA), MVPA, and BMI (or waist circumference), respectively. CONCLUSIONS: In individuals with type 2 diabetes, increasing MVPA, even without achieving the recommended target, is effective in maintaining estimated ß-cell function if sufficient amounts of SED-time are reallocated to LPA.

Mutual Regulation between Redox and Hypoxia-Inducible Factors in Cardiovascular and Renal Complications of Diabetes.

Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes.

Risk of all-cause mortality according to the European Society of Cardiology risk categories in individuals with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study.

AIMS: The 2019 and 2021 European Society of Cardiology (ESC) classifications stratified patients with type 2 diabetes into three categories according to the 10-year risk of death from atherosclerotic cardiovascular disease (ASCVD). The very high-risk category included individuals with established ASCVD, target organ damage (TOD), and/or, in the 2019 classification only, ≥ 3 additional ASCVD risk factors. We assessed risk of all-cause mortality according to the two ESC classifications in the Renal Insufficiency And Cardiovascular Events cohort. METHODS: Participants (n = 15,773) were stratified based on the presence of ASCVD, TOD, and ASCVD risk factors at baseline (2006-2008). Vital status was retrieved in 2015. RESULTS: Less than 1% of participants fell in the moderate-risk category. According to the 2019 classification, ~ 1/3 fell in the high-risk and ~ 2/3 in the very high-risk category, whereas the opposite occurred with the 2021 classification. Mortality risk increased across categories according to both classifications. Among very high-risk patients, mortality was much lower in those with ≥ 3 additional ASCVD risk factors and almost equal in those with TOD and ASCVD ± TOD, using the 2019 classification, whereas it was much higher in those with ASCVD + TOD and, to a lesser extent, TOD only than in those with ASCVD only, using the 2021 classification. CONCLUSIONS: The negligible number of moderate-risk patients suggests that these classifications might overestimate risk of ASCVD death. Downgrading patients with ≥ 3 additional ASCVD risk factors to the high-risk category is consistent with mortality data. Risk of death is very high in the presence of TOD irrespective of established ASCVD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00715481.

Food-Related Carbonyl Stress in Cardiometabolic and Cancer Risk Linked to Unhealthy Modern Diet.

Carbonyl stress is a condition characterized by an increase in the steady-state levels of reactive carbonyl species (RCS) that leads to accumulation of their irreversible covalent adducts with biological molecules. RCS are generated by the oxidative cleavage and cellular metabolism of lipids and sugars. In addition to causing damage directly, the RCS adducts, advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs), cause additional harm by eliciting chronic inflammation through receptor-mediated mechanisms. Hyperglycemia- and dyslipidemia-induced carbonyl stress plays a role in diabetic cardiovascular complications and diabetes-related cancer risk. Moreover, the increased dietary exposure to AGEs/ALEs could mediate the impact of the modern, highly processed diet on cardiometabolic and cancer risk. Finally, the transient carbonyl stress resulting from supraphysiological postprandial spikes in blood glucose and lipid levels may play a role in acute proinflammatory and proatherogenic changes occurring after a calorie dense meal. These findings underline the potential importance of carbonyl stress as a mediator of the cardiometabolic and cancer risk linked to today's unhealthy diet. In this review, current knowledge in this field is discussed along with future research courses to offer new insights and open new avenues for therapeutic interventions to prevent diet-associated cardiometabolic disorders and cancer.

Relationships of Changes in Physical Activity and Sedentary Behavior With Changes in Physical Fitness and Cardiometabolic Risk Profile in Individuals With Type 2 Diabetes: The Italian Diabetes and Exercise Study 2 (IDES_2).

OBJECTIVE: In the Italian Diabetes and Exercise Study_2 (IDES_2), behavioral counseling promoted a sustained increase in physical activity (PA) volume (+3.3 MET h ⋅ week-1), moderate- to vigorous-intensity PA (MVPA) (+6.4 min ⋅ day-1), and light-intensity PA (LPA) (+0.8 h ⋅ day-1) and decrease in sedentary time (SED-time) (-0.8 h ⋅ day-1). Here, we investigated the relationships of changes in PA/SED-time with changes in physical fitness and cardiometabolic risk profile in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this 3-year randomized clinical trial, 300 physically inactive and sedentary patients were randomized 1:1 to receive 1-month theoretical and practical counseling once a year or standard care. Changes in physical fitness and cardiovascular risk factors/scores according to quartiles of accelerometer-measured changes in PA/SED-time were assessed, together with univariate and multivariable associations between these parameters, in the whole cohort and by study arm. RESULTS: Physical fitness increased and HbA1c and coronary heart disease 10-year risk scores decreased with quartiles of MVPA and SED-time change. In quartile IV of MVPA increase and SED-time decrease, cardiorespiratory fitness increased by 5.23 and 4.49 mL ⋅ min-1 ⋅ kg-1 and HbA1c decreased by 0.73 and 0.85%, respectively. Univariate correlations confirmed these relationships, and mean changes in both MPVA and SED-time predicted changes in physical fitness and cardiovascular risk factors/scores independently of one another and of other confounders. Similar findings were observed with LPA and PA volume and in each group separately. CONCLUSIONS: Even modest increments in MVPA may have a clinically meaningful impact, and reallocating SED-time to LPA may also contribute to improved outcomes, possibly by increasing total energy expenditure.

Effect of a Behavioural Intervention for Adoption and Maintenance of a Physically Active Lifestyle on Psychological Well-Being and Quality of Life in Patients with Type 2 Diabetes: The IDES_2 Randomized Clinical Trial.

BACKGROUND: Psychological well-being and quality of life (QoL) are important outcomes of lifestyle interventions, as a positive impact may favour long-term maintenance of behaviour change. OBJECTIVE: This study investigated the effect of a behavioural intervention for adopting and maintaining an active lifestyle on psychological well-being and health-related QoL in individuals with type 2 diabetes. METHODS: Three hundred physically inactive and sedentary patients were randomized 1:1 to receive 1 month's theoretical and practical counselling once a year (intervention group, INT) or standard care (control group, CON) for 3 years. Psychological well-being and QoL, assessed using the World Health Organization (WHO)-5 and the 36-Item Short Form (SF-36) questionnaire, respectively, were pre-specified secondary endpoints. The primary endpoint was sustained behaviour change, as assessed by accelerometer-based measurement of physical activity (PA) and sedentary time. RESULTS: WHO-5 and SF-36 physical and mental component summary (PCS and MCS) scores increased progressively in the INT group and decreased in the CON group, resulting in significant between-group differences (WHO-5: mean difference 7.35 (95% confidence interval (CI) 3.15-11.55), P = 0.0007; PCS 4.20 (95% CI 2.25-6.15), P < 0.0001; MCS 3.04 (95% CI 1.09-4.99), P = 0.0025). Percentage of participants with likely depression decreased in the INT group and increased in the CON group. PA volume changes were independently associated with WHO-5 changes, which were significantly higher in participants who accumulated > 150 min·wk-1 of moderate-to-vigorous intensity PA versus those who did not (13.06 (95% CI 7.51-18.61), P < 0.0001), whereas no relationship was detected for QoL. CONCLUSION: A counselling intervention that was effective in promoting a sustained change in PA and sedentary behaviour significantly improved psychological well-being and QoL. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01600937; 10 October 2012.

Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage.

Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.

Diabetic Complications and Oxidative Stress: A 20-Year Voyage Back in Time and Back to the Future.

Twenty years have passed since Brownlee and colleagues proposed a single unifying mechanism for diabetic complications, introducing a turning point in this field of research. For the first time, reactive oxygen species (ROS) were identified as the causal link between hyperglycemia and four seemingly independent pathways that are involved in the pathogenesis of diabetes-associated vascular disease. Before and after this milestone in diabetes research, hundreds of articles describe a role for ROS, but the failure of clinical trials to demonstrate antioxidant benefits and some recent experimental studies showing that ROS are dispensable for the pathogenesis of diabetic complications call for time to reflect. This twenty-year journey focuses on the most relevant literature regarding the main sources of ROS generation in diabetes and their role in the pathogenesis of cell dysfunction and diabetic complications. To identify future research directions, this review discusses the evidence in favor and against oxidative stress as an initial event in the cellular biochemical abnormalities induced by hyperglycemia. It also explores possible alternative mechanisms, including carbonyl stress and the Warburg effect, linking glucose and lipid excess, mitochondrial dysfunction, and the activation of alternative pathways of glucose metabolism leading to vascular cell injury and inflammation.

Diabetes and Pancreatic Cancer-A Dangerous Liaison Relying on Carbonyl Stress.

Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention and treatment, particularly in high-risk diabetic individuals.

Galectin-3 gene deletion results in defective adipose tissue maturation and impaired insulin sensitivity and glucose homeostasis.

Adiposopathy is a pathological adipose tissue (AT) response to overfeeding characterized by reduced AT expandability due to impaired adipogenesis, which favors inflammation, insulin resistance (IR), and abnormal glucose regulation. However, it is unclear whether defective adipogenesis causes metabolic derangement also independently of an increased demand for fat storage. As galectin-3 has been implicated in both adipocyte differentiation and glucose homeostasis, we tested this hypothesis in galectin-3 knockout (Lgal3-/-) mice fed a standard chow. In vitro, Lgal3-/- adipocyte precursors showed impaired terminal differentiation (maturation). Two-month-old Lgal3-/- mice showed impaired AT maturation, with reduced adipocyte size and expression of adipogenic genes, but unchanged fat mass and no sign of adipocyte degeneration/death or ectopic fat accumulation. AT immaturity was associated with AT and whole-body inflammation and IR, glucose intolerance, and hyperglycemia. Five-month-old Lgal3-/- mice exhibited a more mature AT phenotype, with no difference in insulin sensitivity and expression of inflammatory cytokines versus WT animals, though abnormal glucose homeostasis persisted and was associated with reduced ß-cell function. These data show that adipogenesis capacity per se affects AT function, insulin sensitivity, and glucose homeostasis independently of increased fat intake, accumulation and redistribution, thus uncovering a direct link between defective adipogenesis, IR and susceptibility to diabetes.

Renal protection with glucagon-like peptide-1 receptor agonists.

There is an unmet need for renoprotective drugs for more pronounced reduction of albuminuria beyond that provided by renin-angiotensin system (RAS) blockers and for effective slowdown of eGFR decline independent of albuminuria. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have proven effective in reducing prespecified secondary composite kidney outcomes in cardiovascular outcome trials. However, GLP-1 RAs showed a prevailing anti-albuminuric effect, additional to that of RAS blockers, and a non-significant risk reduction in worsening of kidney function, at variance with sodium-glucose cotransporter 2 inhibitors. Mechanisms underlying renal protection with GLP-1 RAs are porly understood. Though treatment with GLP-1 RAs resulted in better glycaemic, blood pressure and body weight control versus placebo, correction for on-trial changes in these parameters did not significantly affect results. Anti-inflammatory/anti-oxidant effects via intracellular signalling through protein kinase A, natriuretic effect via inhibition of sodium-hydrogen exchanger 3 and reduction of hyperfiltration have been proposed as direct renoprotective effects.